Aging is characterized by progressive, degenerative changes in many organ systems. Reproductive aging is an early and striking example of these changes that results in birth defects and infertility in women. Age-related degeneration of somatic tissues is a major contributor to disability and death. Treatments that extend human health span and lifespan are desirable, but no drugs that delay normal age-related degeneration are available. It is a high priority to develop new therapeutic approaches. The long-term objectives of this proposal are to characterize endogenous pathways that influence longevity and identify drugs that delay age- related degeneration. The results will have a sustained impact by elucidating mechanisms that control aging and suggesting new therapeutic strategies for age-related pathology. We used the powerful C. elegans model system to discover FDA-approved drugs and genetic mutations that can extend the lifespan of worms. The C. elegans germ line contains a population of adult stem cells, and we demonstrated that this cell population displays age-related decline, establishing C. elegans as a model of stem cell aging. Studies conducted during the previous project period support three innovative hypotheses. (1) The lifespan extension caused by captopril is mediated by the acn-1 gene, and the acn-1 pathway is an evolutionarily conserved mediator of lifespan control. (2) A rapid, age-related decline of germ line stem cell function contributes to reproductive aging, and an age-related decline in the GLP-1/Notch signaling pathway may control this decline. (3) Triggering the innate immune response and food avoidance behavior can delay age-related degeneration and extend lifespan. To test these hypotheses, we propose three specific aims. Aim 1. Characterize the mechanism of action captopril and the acn-1 gene in extending the adult life span of worms. This aim is significant because it can result in the identification and characterization of new endogenous pathways that modulate the rate of aging. Furthermore, it will establish the foundation for evaluating how ACE inhibitor drugs might be used therapeutically to delay age-related degeneration. Aim 2. Test the hypothesis that age-related declines in germ line stem cells contribute to reproductive aging. We will establish the time course of age-related changes in signaling pathways that control germ line size, use genetic approaches to test the function of GLP-1/Notch signaling, and analyze the mechanisms of genes and drugs that delay reproductive aging. Aim 3: Characterize the mechanism of action of phm-2 and eat-2 in lifespan extension by analyzing transcriptional changes in mutant animals. The function of the innate immune response and food avoidance behavior will be determined using genetic studies. By combining molecular and genetic approaches, these studies will elucidate mechanisms of aging, advance the field of aging pharmacology and address important gaps in the current understanding of reproductive aging. Significantly, these studies will establish new therapeutic strategies for addressing age-related degenerative changes in humans.